The objective of this research project is to understand the genetic basis of alcohol-seeking behavior. To this end we have established, through selective breeding from the Wistar rat, high alcohol preference (P) and low alcohol preference (NP) lines. We are also selecting for high and low alcohol preference lines (HAD and LAD, respectively) from the heterogeneous stock N/Nih rat. The P rat has been shown to satisfy the major criteria for an animal model of alcoholism. A number of neurochemical, behavioral (in response to ethanol) and biochemical differences between the P and NP lines have been found. These findings have suggested hypotheses for the neurobiological basis of alcohol-seeking behavior that can be tested with use of these genetically developed animals. A major objective of this research component in the next 5 years will be the evaluation of whether the already-discovered and other yet-to-be-discovered traits and genetic markers that differentiate P from NP rats are genetically related to alcohol-seeking behavior. This will be accomplished by segregation analysis in F, backcrosses to the parental lines and in the F(2) offspring of the P and NP lines. To this end, we are also proposing a new initiative that will search for new genetic markers of alcohol preference and, in collaboration with the other research components, apply molecular biological techniques (in situ hybridization) to the study of the neurobiology of alcohol-seeking behavior. The molecular biology studies will include the use of cDNA probes for the major histocompatibility locus (there appears to be an association of this locus with alcohol preference) and 'candidate' genes such as those for renin, the serotonin, dopamine and GABA receptors and enzymes of monoamine synthesis and metabolism. Another newly discovered association of alcohol preference is a variant isoenzyme form of mitochondrial aldehyde dehydrogenase (ALDH2). The nature of this protein polymorphism, the properties of the variant ALDH2 and its relation to alcohol preference will be explored. Assessment of the generality of the associated traits of high alcohol-seeking behavior discovered in the P/NP rats will be performed through studies in the HAD and LAD lines.